The present invention relates to a rapid-acting insulin formulation.
Since the production of insulin by genetic engineering, at the beginning of the 1980s, diabetic patients have had the benefit of human insulin for their treatment. This product has greatly improved this therapy since the immunological risks associated with the use of nonhuman, in particular porcine, insulin are eliminated. However, human insulin injected subcutaneously only has a hypoglycemic effect after 60 minutes, which means that diabetic patients treated with human insulin must carry out the injection 30 minutes before a meal.
One of the problems that need to be solved for improving the health and comfort of diabetic patients is to make insulin formulations available that provide a hypoglycemic response more quickly than that of human insulin and if possible approaching the physiological response of a healthy individual. The endogenous insulin secretion in a healthy individual is triggered immediately by an increase in glycemia. The objective is to reduce as much as possible the delay between injection of insulin and the start of a meal.
It is now accepted that making such formulations available is useful so that management of the disease is optimal.
Genetic engineering has made it possible to provide a response with the development of rapid-acting insulin analogs. These insulins are modified on one or two amino acids so that they are absorbed more rapidly in the blood compartment after a subcutaneous injection. These insulins lispro (Humalog®, Lilly), aspart (Novolog®, Novo) and glulisine (Apidra®, SanofiAventis) are stable insulin solutions with a more rapid hypoglycemic response than that of human insulin. Therefore patients treated with these rapid-acting insulin analogs can proceed with insulin injection just 15 minutes before a meal.
The principle of the rapid-acting insulin analogs is to form hexamers with a concentration of 100 IU/mL for ensuring stability of the insulin in the commercial product while promoting very rapid dissociation of these hexamers into monomers after subcutaneous injection in order to obtain rapid action.
Human insulin as formulated in its commercial form does not allow a hypoglycemic response to be obtained that is close in terms of kinetics of the physiological response generated by the start of a meal (increase in glycemia), because at the concentration of use (100 IU/mL), in the presence of zinc and other excipients such as phenol or m-cresol, it assembles in the hexamer form whereas it is active in the form of monomer and of dimer. Human insulin is prepared in the form of hexamers so that it is stable for nearly 2 years at 4° C., since in the form of monomers it has a very strong tendency to aggregate and then to form fibrils, which causes it to lose its activity. Moreover, in this aggregated form, it presents an immunological risk for the patient.
Dissociation of the hexamers into dimers and of the dimers into monomers delays its action by nearly 20 minutes compared with a rapid-acting insulin analog (Brange J., et al., Advanced Drug Delivery Review, 35, 1999, 307-335).
The kinetics of passage of insulin analogs into the blood, and their kinetics of reduction of glycemia, are not optimal and there is a real need for a formulation having an even shorter time of action in order to approach the kinetics of endogenous insulin secretion in healthy persons.
The company Biodel has proposed a solution to this problem with a formulation of human insulin comprising EDTA and citric acid as described in patent application US200839365. EDTA, by its capacity for complexing zinc atoms, and citric acid, by its interactions with the cationic zones present on the surface of insulin, are described as destabilizing the hexameric form of insulin and thus reducing its time of action.
However, such a formulation notably has the drawback of dissociating the hexameric form of insulin, which is the only stable form able to meet the stability requirements of the pharmaceutical regulations.
PCT application WO2010/122385, in the name of the applicant, is also known; this describes formulations of human insulin or insulin analog for solving the various problems mentioned above by adding a substituted polysaccharide comprising carboxyl groups.
However, the requirements arising from chronic and intensive use or even pediatric use of such formulations lead a person skilled in the art to try to use excipients whose molecular weight and size are as small as possible to facilitate their elimination.
The aim of reducing the size of the polysaccharides has led a person skilled in the art to consider oligosaccharides, but owing to their reduced size these do not have the same properties as the polysaccharides, since there is loss of the polymer effect, as is demonstrated in the comparative examples in the experimental section, see notably the tests for insulin dissolution at the isoelectric point and the tests of interaction with a model protein such as albumin.